Role of gp91phox-containing NADPH oxidase in the deoxycorticosterone acetate-salt-induced hypertension

Fujii, Aya; Nakano, Daisuke; Katsuragi, Miyuki; Ohkita, Mamoru; Takaoka, Masanori; Ohno, Yukihiro; Matsumura, Yasuo

doi:10.1016/j.ejphar.2006.09.039

Cited by 32 publications

(30 citation statements)

References 23 publications

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“…As previously reported, 37,38 we found that DOCA-salt treatment in mPGES-1 WT mice induced modest hypertension as determined by both tail-cuff and telemetry. Sodium accumulation in these mice was less significant than that in the KO mice.…”

Section: Discussionsupporting

confidence: 67%

mPGES-1 Protects Against DOCA-Salt Hypertension via Inhibition of Oxidative Stress or Stimulation of NO/cGMP

2010

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Abstract-Microsomal prostaglandin E synthase-1 (mPGES-1) is a recently characterized cytokine-inducible enzyme critically involved in pain and inflammatory response. However, its role in blood pressure regulation is still debatable. The present study was undertaken to examine the effect of mPGES-1 deletion on DOCA-salt hypertension. After 2 weeks of DOCA plus 1% NaCl as drinking fluid, hypertension and sodium retention were more severe in mPGES-1 knockout (KO) mice than in wild-type (WT) controls. The indices of oxidative stress including urinary 8-isprostane and renal thiobarbituric acid-reactive substances were only modestly increased or unchanged in the WT mice but more significantly increased in the KO mice after DOCA-salt. Conversely, in response to DOCA-salt, the indices of antioxidant systems including renal expression of superoxide dismutase-3 and urinary nitrate/nitrite excretion were all significantly elevated in the WT mice but remarkably suppressed in the KO mice. Tempol treatment (50 mg/kg per day) in DOCA-salt KO mice produced a marked attenuation of hypertension, sodium retention, and kidney injury. Immunoblotting demonstrated increased renal expression of mPGES-1 in DOCA-salt WT mice. DOCA-salt induced a nearly 5-fold increase in urinary PGE 2 excretion in the WT mice, and this increase was completely abolished in the KO mice. Together, these results suggest that mPGES-1-derived PGE 2 confers protection against DOCA-salt hypertension likely via inhibition of oxidative stress or stimulation of superoxide dismutase-3 and urinary nitrate/nitrite system. Key Words: cGMP Ⅲ DOCA-salt hypertension Ⅲ mPGES-1 Ⅲ nitric oxide Ⅲ oxidative stress P rostaglandin E 2 (PGE 2 ) is a major product of arachidonic acid metabolism, being implicated in pain and inflammatory responses and in regulation of various physiological functions. 1 In particular, PGE 2 is a natriuretic and diuretic factor and therefore is antihypertensive. 2,3 To date, at least 3 major forms of prostaglandin E synthase (PGES) have been cloned: membrane-associated PGES (mPGES)-1, mPGES-2, and cytosolic PGES. 4,[5][6][7][8]9,10,11,12 Mice deficient in mPGES-1 but not mPGES-2 or cytosolic PGES suppress PGE 2 production, suggesting that mPGES-1 may represent the only enzymatic pathway capable of generating PGE 2 in vivo. 13,14,15,16,17 Several recent studies using mPGES-1 knockout (KO) mice demonstrate a major role of mPGES-1 in pain and inflammatory responses. 13,14 The cardiovascular consequences associated with COX-2 inhibitors 18 -21,22,23 have stimulated the interest in mPGES-1 as a potential target of the next generation of anti-inflammatory drugs. 24 Therefore, it is critically important to determine whether mPGES-1 plays a physiological role in the cardiorenal system similar to COX-2.The use of a synthetic mineralocorticoid, DOCA, which is an aldosterone analog, together with a high-salt diet (DOCAsalt), is a well-established means of inducing hypertension. This hypertension model is relevant to human primary aldosteronism. The relevance t...

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Section: Discussionsupporting

confidence: 67%

mPGES-1 Protects Against DOCA-Salt Hypertension via Inhibition of Oxidative Stress or Stimulation of NO/cGMP

2010

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“…2); however, no Nox catalytic subunits were present in mitochondrial samples. These data are in agreement with previously reported localization of Nox subunits in the cytoplasm and nucleus but not in the mitochondria (13,27 -and hypertension, we have used Nox2 knockout mice (gp91phox KO) (22). Nox2KO and wildtype littermates (C57Bl/6J) were infused for 10 days with saline (vehicle) or AngII (0.7 mg/kg/day).…”

supporting

confidence: 79%

Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension

Dikalov

Nazarewicz

Bikineyeva

et al. 2014

Antioxidants & Redox Signaling

264

203

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Aims: Angiotensin II (AngII)-induced superoxide (O 2 -) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O 2 -and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension. Results: Western blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII-induced O 2 -production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngIIinduced cellular and mitochondrial O 2 -and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O 2 -production. Inhibition of the mitochondrial ATP-sensitive potassium channel (mitoK

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“…Induction of hypertension by deoxycorticosterone acetate (DOCA) salt was impaired in Nox-deficient mice [75,76]. Physiologically, Nox proteins are expressed in the macula densa [77] and may contribute to tubuloglomerular feedback.…”

Section: Hypertensionmentioning

confidence: 99%

The Nox Family of NADPH Oxidases: Friend or Foe of the Vascular System?

2011

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NADPH (nicotinamide adenine dinucleotide phosphate) oxidases are important sources of reactive oxygen species (ROS). In the vascular system, ROS can have both beneficial and detrimental effects. Under physiologic conditions, ROS are involved in signaling pathways that regulate vascular tone as well as cellular processes like proliferation, migration and differentiation. However, high doses of ROS, which are produced after induction or activation of NADPH oxidases in response to cardiovascular risk factors and inflammation, contribute to the development of endothelial dysfunction and vascular disease. In vascular cells, the NADPH oxidase isoforms Nox1, Nox2, Nox4, and Nox5 are expressed, which differ in their activity, response to stimuli, and the type of ROS released. This review focuses on the specific role of different NADPH oxidase isoforms in vascular physiology and their potential contributions to vascular diseases.

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Role of gp91phox-containing NADPH oxidase in the deoxycorticosterone acetate-salt-induced hypertension

Cited by 32 publications

References 23 publications

mPGES-1 Protects Against DOCA-Salt Hypertension via Inhibition of Oxidative Stress or Stimulation of NO/cGMP

mPGES-1 Protects Against DOCA-Salt Hypertension via Inhibition of Oxidative Stress or Stimulation of NO/cGMP

Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension

The Nox Family of NADPH Oxidases: Friend or Foe of the Vascular System?

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